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Germline variant in SLCO2B1 and response to abiraterone acetate plus prednisone (AA) in new onset metastatic castration-resistant prostate cancer (mCRPC)

ABSTRACT: Germline variant in SLCO2B1 and response to abiraterone acetate plus prednisone (AA) in new onset metastatic castration-resistant prostate cancer (mCRPC)

PROVIDER: PRJNA509610 | ENA |

REPOSITORIES: ENA

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Germline variant in SLCO2B1 and response to abiraterone acetate plus prednisone (AA) in new onset metastatic castration-resistant prostate cancer (mCRPC)

Project description:There are many treatment options available for men with metastatic castration-resistant prostate cancer (mCRPC). Yet, biomarkers predictive of differential response to treatment are currently available. A recent translational study suggested that SLCO2B1 genotype could predict response to abiraterone acetate (AA) for men with advanced prostate cancer. Here, we investigate whether germline variants in SLCO2B1 are predictive of response to first-line AA in men with new mCRPC. Clinical data and samples were analyzed from a prospective prostate cancer registry at the University of Utah. Genotyping was performed using the Illumina OmniExpress genotyping platform. Primary endpoint was progression-free survival (PFS) on first-line AA in men with mCRPC. We performed a pre-speciﬁed multivariate Cox regression analysis to assess the independent predictive value of rs12422149 and rs1789693 on PFS on AA. Of 401 men with advanced prostate cancer genotyped, 323 were homozygous wild type for rs12422149 (80.5%), 74 were heterozygous (18.5%), and 4 were homozygous variant (1.0%). In a multivariate analysis of 79 men treated with first-line AA for mCRPC, men heterozygous for rs12422149 had significantly improved median PFS compared to the homozygous wild-type group (8.9 months vs. 6.3 months, HR 0.46, 95% CI 0.23-0.94, p=0.03). No significant difference in median PFS was seen by rs1789693 genotype. In this first clinical validation of translational data reported by Mostaghel and colleagues, germline variant alleles in rs12422149 of SLCO2B1 are common and predict improved response to first-line AA In men with mCRPC.

2018-12-13 | GSE123695 | GEO

Characterization of an abiraterone ultra-responsive phenotype in castration-resistant prostate cancer patient-derived xenografts

Project description:To identify the molecular signature associated with abiraterone acetate (AA) response and mechanisms underlying AA resistance in castration-resistant prostate cancer patient-derived xenografts (PDXs).

2016-12-22 | GSE85672 | GEO

Cell-free DNA modification dynamics in abiraterone acetate-treated prostate cancer patients

Project description:Purpose: Primary resistance to abiraterone acetate (AA), a key medication for the treatment of metastatic castration-resistant prostate cancer, occurs in 20-40% of the patients. We aim to identify predictive biomarkers for AA-treatment response and understand the mechanisms related to treatment resistance. Experimental Design: We used the Infinium Human Methylation 450K BeadChip to monitor modification profiles of cell-free circulating DNA (cfDNA) in 108 plasma samples collected from 33 AA-treated patients. Results: Thirty cytosines showed significant modification differences (FDR q < 0.05) between the AA-sensitive and AA-resistant patients during the treatment, of which 21 cytosines were differentially modified prior to treatment. In addition, the AA-sensitive patients, but not AA-resistant patients, lost interindividual variation of cfDNA modification shortly after starting AA-treatment, but such variation returned to initial levels in the later phases of treatment. Conclusions: Our findings provide a list of potential biomarkers for prediction of AA-treatment response, highlight the prognostic value of using cytosine modification variance as biomarkers, and shed new insights into the mechanisms of prostate cancer relapse in AA-sensitive patients.

2018-03-20 | GSE108462 | GEO

Abiraterone acetate and di-n-butyl phthalate (DBP) response in a human fetal testis xenograft bioassay

Project description:The goal of this study was to determine the effects of a well-characterized anti-androgen, abiraterone acetate, and a suspected human anti-androgen, di-n-butyl phthalate (DBP) on the androgenic function of human fetal testis. Human fetal testis was xenografted into the renal subcapsular space of castrated male athymic nude mice. Hosts were treated with hCG to stimulate testosterone production in the xenografts, and were concurrently treated with either abiraterone acetate or DBP. While abiraterone acetate (14 d, 75 mg/kg/d p.o.) dramatically reduced testosterone and the weights of androgen-sensitive host organs, DBP (14 d, 500 mg/kg/d p.o.) had no effect on androgenic endpoints. Three paired analyses were performed using the LIMMA package in R (commands lmfit and eBayes), with the Benjamini-Hochberg correction for multiple comparisons (Smyth 2005): vehicle-treated xenografts vs. unimplanted testis (n=5), abiraterone-treated xenografts vs. matched control xenografts (n=3), and DBP-treated xenografts vs. matched control xenografts (n=3). There were significant differences in gene expression between grafted and ungrafted samples, including dramatic upregulation of microRNAs. Gene expression analysis also showed that abiraterone decreased expression of genes related to cell differentiation, while DBP induced expression of oxidative stress response genes and decreased expression of factors related to embryonic development. 17 xenograft samples were analyzed, including 5 unimplanted samples, 6 vehicle treated xenografts, 3 abiraterone acetate-treated xenografts, and 3 DBP-treated xenografts. Samples were paired (derived from the same donor tissue) for each comparison: vehicle vs. unimplanted (n=5), abiraterone vs. vehicle (n=3), and DBP vs. vehicle (n=3).

2013-10-31 | E-GEOD-49244 | biostudies-arrayexpress

Abiraterone acetate and di-n-butyl phthalate (DBP) response in a human fetal testis xenograft bioassay

2013-10-31 | GSE49244 | GEO

Effect of abiraterone acetate plus prednisone on the QT interval in patients with metastatic castration-resistant prostate cancer.

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Economic Outcomes in Patients with Chemotherapy-Naive Metastatic Castration-Resistant Prostate Cancer Treated with Enzalutamide or Abiraterone Acetate Plus Prednisone.